DESCRIPTION: With traumatic spinal cord injury (SCI) cellular organization at the injury site is profoundly disturbed. Many cells die, the survivors alter their programs of gene activity and thus their appearance and function. Two opposing forces go into play that influence the long-term consequences of injury. Secondary injury mechanisms act to exacerbate the loss of cells and functional capacity. At virtually, the same time, mechanisms that support recovery begin to operate, mechanisms that, at least in the case of incomplete injuries, lead to significant reductions in functional deficits over time. We postulate that an altered conversation between cells in the injured spinal cord is involved in both processes. In this initial project period we will focus on the communication mediated by axons. Our goal will be to investigate the role of axonal activity (impulse conduction) in secondary injury and recovery processes after conducive SCI. We will use a well- characterized rate model of clinically relevant conducive SCI and experimentally modify axonal activity, i.e., impulse conduction, with the sodium channel blacker tetrodotoxin (TTX). Our first hypotheses is that: axonal Na+ channels that are the basis for impulse conduction are also causally involved in acute axonal pathology at the injury site that leads to loss of white matter. To test this hypothesis we will use light and electron microscopy to quantitatively assess acute axonal pathology and chronic loss of white matter in the presence and absence of acute microinjection of TTX. We will also assess the effects of other drugs that we postulate will block downstream events leading to secondary injury of white matter. As white matter injury is key to the profound effects of SCI, and little is currently known of the mechanisms involved in vivo, these studies are crucial to identifying the types of agents that might be of eventual therapeutic use. Our second hypothesis is that: alterations in axon impulse conduction also lead to effects distal to the injury site that contribute, in ways beyond the loss of descending control pathways, to both acute and chronic functional impairment. We will determine effects of treatment with TTX, and other drugs, on initial arreflexia after SCI, on the time course and degree of functional recovery. Activity-dependent processes have been clearly shown to be important in development and in plasticity of the adult CNS. Understanding their role in the partial functional recovery seen after incomplete SCI will provide the basis for new strategies to enhance functional recovery after SCI and obtain the greatest possible function form tissue spared by the trauma.